• β-blockers
• Adrenergic Agonists
• Calcium channel blockers

• compete with β-adrenergic agonists for available β sites
• at least 2 types of β adrenergic receptors, β₁ and β₂
• β₁ receptors are located mainly in the myocardium, kidney and eye
• β2 receptors located mainly in adipose, lung, pancreas, liver, smooth and skeletal muscle

• B₁ 
• β antagonist effects: 
  • ↓heart rate
  • ↓contractility
  • ↓ conduction

• B₁ 
• β antagonist effects: 
  • ↓ renin secretion

• B2 
• β antagonist effects: 
  • ↓ peripheral vascular resistance (peripheral vasodilation)

• B2 
• β antagonist effects: 
  • Inhibit glycogenolysis (during hypoglycemia)
  • Inhibit insulin secretion (during hyperglycemia)

• B2 
• β antagonist effects: 
  • bronchoconstriction

• Beta blockers that have local anesthetic or membrane stabilizing activity (affects cardiac AP), similar to lidocaine, that is independent of beta blockade
• not significant at usual doses of these agents
• this effect may be important when there is an overdose
• all β blockers exert membrane stabilizing activity on cardiac cells when given in large doses. This activity important wen anti-arrhythmic properties are needed

• beta blockers that activate beta receptors partially in the absence of catecholamines
• For example, this slight residual activity may prevent profound bradycardia or negative inotropy in a resting heart. (if heart rate is dangerously low ISA may be protected by β-blockers)
• clinical advantage is unclear and may be disadvantageous in the context of 2º prevention of MI
• despite the dheoretical advantages of ISA agents, they do NOT appear to reduce cardiovascular events as well as other β blockers

• Nadolol: low 
• Pindolol: low 
• Propranolol: high 
• Timolol: low to moderate 
• Sotalol: low 
• Penbutolol: High 

• Acebutolol:  Low
• Atenolol: Low
• Bisoprolol: Low
• Esmolol: Low
• Metoprolol: Moderate
• Betaxolol: Moderate

• Carteolol: Low
• Carvedilol*: Moderate
• Labetalol*: Low

• little effect on the normal heart of an individual at rest, but profound effects when sympathetic control of the heart is dominant (ie., exercise or stress)
• by ↓ the effects of catecholamines on the heart, β blockers ↓:
  • myocardial contractility, heart rate, conduction in the atria and AV node, cardiac output
• also block beta receptors of the renal juxtaglomerular complex, reducing renin secretion and diminishing production of circulating Ang II
• Cause a delayed fall in peripheral vascular resistance which may partially account for their anti-hypertensive effect

• non selective Beta blockers block β₂ receptors in bronchial smooth muscle. 
  • little effect on pulmonary fxn in normal individuals
  • can lead to life threatening bronchoconstriction in pts with asthma/COPD 

• Can only use β₁ selective blockers in patients with controlled COPD. DO NOT use if COPD is uncontrolled
• DO NOT use in asthmatic patients unless if absolutely necessary and only useβ₁ selective blockers

• inhibit glycogenolysis (most critical during hypoglycemia)
• interfere with counter regulatory effects of catecholamines secreted during hypoglycemia by blunting the perception of symptoms (ie, tremor, tachycardia, nervousness. Diaphoreses (sweating) not affected

• non-selective β blockers consistently ↓HDL, ↑LDL, and ↑ triglycerides (not clinically significant)
• In contrast ,β₁ selective blockers, produce similar effect but less pronounced on HDL (better for pts with hyperlipidemia) 
• Agents with sig. ISA produce a lower degree of lipid abnormalities compared to β blockers without ISA.
  • Pindolol and acebutolol are agents with ISA that are lipid neutral
• Acebutolol, labetolol, and Carvedilol are also lipid neutral. 
  • Carvedilol and labetolol are nonslective, but do not have effects on lipids, so use if concerned with lipids. However if concerned with selectivity, use β₁ selective agent 1st

• dose-dependent: at higher doses, cardioselecive agents lose their relative selectivity for β₁ receptors and block β₂ receptors as effectively

• cardioselective agents are preferred
• β blockers attenuate the normal physiologic response to hypoglycemia

• related to 1st pass metabolism, t_1/2, degree of lipophilicity, and route of elimination
  • Propranolol and metoprolol undergo extensive 1st pass metabolism (given at different IV vs oral doses)
  • Atenolol, nadolol, and sotalol have relatively short t_1/2 and excreted renally
  • t_1/2 of β blockers does not necessarily correlate well with duration of action

• Penetrate better into the CNS. This may be an disadvantage (increased drowsiness and dizziness) or an advantage (e.g., migraine, essential tremor)
• BP lowering is = among beta blockers regardless of lipophilicity 

During heart failure, catecholamines are increased, resulting in reshaping of the heart tissue (loses elasticity)

• beta blockers reduce this effect

• Direct acting a₁ agonist
• Causes vasoconstriction of arterioles and systemic arterial vasoconstriction, ↑ BP, ↑ systemic vascular resistance, ↓ renal perfusion, and may ↓ cardiac output
• Used as a pressor in ICU and locally as nasal decongestant and a mydriatic agent to facilitate visualization of the retina

• local IV extravasation causes necrosis
  • strong vasoconstriction effect causes small vessels to rupture. Give in central line
• ↓ urine output, reflex bradycardia, ↓ cardiac output

• Racemic mixture
• β₁ and α₁ agonist activity 
• causes ↑ contractility and ↑HR, net effect on systemic vascular resistance
• Used as an inotropic agent (due to B₁ effects)

• Hypertension
• slight tachycardia
• tachyarrhythmias (facilitates AV conduction)
• minor ↑ BP

• Stimulates α₁α₂β₁β₂ receptors
• results in relaxation of smooth m. of the bronchial tree, cardiac stimulation, and dilation of skeletal m. vasculature
• Causes ↑HR, ↑ C.O, ↑ O₂ consumption
• 1º use is as myocardial stimulant in CPR
• Different effects at low and high doses

• acts 1º as β agonist
•  producing inotropy and vasodilation

• mixed α and β stimulation 
•  α effects predominate, masking β₁ cardiac effects due to the intense vasoconstriction

• arrhythmia
• ↓ renal blood flow
• ↑ lactate (lactate = indicator of mortality, pts in ICU with increased levels of lactate have greater chance of death. DO NOT give as pressor to these patients

• stimulates α₁β₁ receptors
• more effective in reversing hypotension than dopamine in pts with shock
• In severe hypotension, NE does not normally produce reflex bradycardia and the C.O. is well maintained
• does not worsen serum lactate levels
• drug of choice for ICU pts

• Necrosis and sloughing at IV site
• ↓ renal blood flow

• Acts on D₁β₁α₁ receptors
• given at 3 different doses (low, moderate, high) each which produces a different effect

Acts on D₁ receptors and cause vasodilation in renal and mesenteric vessels

• Up to 3 mcg/Kg/min

Exerts positive inotropic effects (↑ contractility of the heart) by stimulating β₁ receptors in the myocardium

• 5-10 mcg/Kg/min

acts as a pressor by generally stimulating α₁ receptors and causing vasoconstriction

• > 10 mcg/Kg/min

• Oral selective presynaptic α₂ agonist
• produces suppression of sympathetic activity and causes ↓ in BP
• used for Hypertension, control of withdrawal symptoms from a number of substances (ie alcohol, nicotine, narcotics)

• dry mouth, sedation, sexual dysfunction
• withdrawal syndrome: rebound hypertension, nervousness, agitation, headache,and confusion upon abrupt discontinuation after long-term therapy. Gradually reduce the dose over 2-4 days to avoid these symptoms

• Phenylalkylamines 
• Benzothiazepines
• Dihydropyridines
• Diarylmaminopropylamines

 Amlodipine, felodipine, isradipine, nicardipine, nifedipine, disoldipine, nimodipine*

*Nimodipine relaxes the cerebral vasculature

Bepridil - has some Na+ channel blocking activity

• CCB bind and inhibit Ca²⁺ channel fxn
• CCB reduce frequency of opening of Ca²⁺ channel in response to depolarization
• Have little effect on most venous beds so don't affect cardiac preload significantly
• result is marked ↓ in transmembrane Ca²⁺ current which effects smooth and cardiac muscle

• Due to the marked ↓ in transmembrane Ca²⁺ current
• Smooth muscle: relaxation
• Cardiac muscle: ↓ contractility, ↓ in SA node rate, ↓ in AV node conduction velocity

• supraventricular tachyarrhythmias: verapamil or diltiazem
• Angina (unstable, exertional, stable): dihydropyridines
• Hypertension: dihydropyridines
• Subarachnoid hemorrhage: nimodipine
• Unlabeled uses:
  • Migraine headache (verapamil)
  • Pulmonary hypertension
  • Raynaud's phenomenon

• Bradycardia, AV block, exacerbation of HF (mostly verapamil and diltiazem), and asystole (rare)
• Excessive vasodilation (dizziness, hypotension, headache, flushing, peripheral edema): particularly dihydropyridines
• constipation: all especially verapamil
• muscle cramps: nimodipine

• Nitroglycerin (SL, IV, PO, ointment, transdermal, lingual spray)
• Isosorbide dinitrate (ISDN)
• Isosorbide mononitrate (ISMN): active metabolite of ISDM
• Amyl nitrite: not clinically used due to side effects

All have same mech. of action and toxicities

• Nitrates: esters of nitric acid (-C-O-NO₂)
• e.g. nitroglycerin, Isosorbide dinitrate

Nitroglycerin (NTG) is prototype

• vascular smooth muscle relaxation
• low [NTG] preferentially dilate the veins more than arterioles
• cause ↓ in ventricular preload (beneficial in HF as it ↓ O₂ demand)
• Higher dose cause further venous pooling and may ↓ systolic and diastolic BO, afterload and cardiac output

• relaxation of smooth muscle of bronchi, GI tract (including biliary system), and genitourinary tract has been demonstrated experimentally
• because of brief duration, these actions of nitrates are rarely of clinical value

Adverse effects of nitrates

• Headache (due to dilation of meningeal arterial vessels)
• Orthostatic hypotension (due to ↑ venous capacitance)
• flushing in face and neck (due to arteriolar vasodilation)
• reflex tachycardia and ↑ cardiac contractility ( indirect effects of ↓ arterial pressure)

• loss of 50% or greater of initial response
• all dosage forms implicated
• proposed mechanisms relate to:
  • endothelial dysfunction
  • superoxide anion production
  • neuorhormonal activation
• Tolerance to NTG causes cross-tolerance to other nitrates

1. Dosing regimen manipulation
2. Thiol/sulhydryl donors (e.g. N-acetylcystiene)
   • not clinically successful
3. Captopril (a sulfhydryl-containing agent)
   • other ACE inhibitors may be beneficial
4. Hydralazine-nitrate combination
   • Hydralazine has antioxidant properties

• nitrate free period of 8-12 hours is needed, (therefore not given every  or 12 hrs)
• Dose escalation may overcome tolerance

Nitrate patches: apply daily remove 12 hrs later

ISDN regular release: BID 8am-2-pm,

TID 8am-1pm-6pm

ISDN SR: 8am-2pm

ISMN: Imdur 8am, Ismo 8am-3pm (7 hrs apart)

Categories of renal pharmacology

Used for Chronic kidney disease (CKD)

• Erythropoiesis-stimulating agents (ESA)
• Iron repletion
• Phosphate binders
• vitamin D
• Calcimimetics

• Epoetin alfa, recombinant (erythropoietin: EPO) [epogen or procrit]
• Darbepoetin [Aranesp]
• Methoxy polyethylene glycon-epoetin beta [Mircera]

• anemia develops as early as stage 3 (Clcr of 30-60 ml/min) of CKD
• caused by ↓ biosynthesis of erythropoetin (EPO) form the kidney

• less transfusion-related problems (infections, iron overload, sensitization) 
• improved cardiovascular and cognitive fxn

• Erythorpoeitin is an glycoprotein that stimulates RBC production. It stimulates the division and differentiation of committed erythroid progenitors in the bone marrow
• Epoetin alfa is manufactured by recombinant DNA tech and has the same biological effects as endogenous EPO

• A hyperglycoslyated analogue of recombinant human erythropoietin 
• its structure results in slower plasma clearance a longer t1/2, and greater in vivo biologic activity compared to epoetin alfa, enabling less frequent dosing (e.g. 1 vs. 3 times week)

• these patients experienced greater risk for death and serious cardiovascular events with administered ESA to target higher vs. lower hemoglobin levels (do not overdo target Hgb)
• individualize dosing to acheive and maintain hemoglobin levels with in the range of 10-12 g/dL

• particular concern in pts with Hg 12 g/dL or greater
• may have shortened survival and time to tumor progression and increased risk of serious cardiovascular and thomboembolic events
• use lowest ESA dose needed to avoid RBC transfusions

Approach to lack/loss of response to ESA therapy

• If lack of response seen look at the following conditions before ↑ ESA levels
• Iron status (supplement with iron if serum [ferritin] is below 100 mg/L or whose serum transferrin saturation is below 20%)
• Infection, inflammatory or malignant processes
• pure red cell aplasia (PRCA) = Rare

• development of neutralizing Ab to endogenous erythropoietin
• see loss of response to therapy, severe anemia, and low reticulocyte counts

• an adequate response to ESAs requires the maintenance of sufficient iron stores
• CKD pts. require iron supplementation due to:
  • impaired erythropoiesis
  • Phlebotomy (e.g hemodialysis)
  • GI bleeding
  • ESA depletes iron stores in order to make iron-containing RBCs

• oral iron not usually utilized b/c of its GI side effects, interaction with other drugs and lack of overall efficacy
• IV iron products preferred, especially in hemodialysis pts. 
• k/DOQI guidelines: administration of IV iron when serum ferritin is up to 500 ng/ml

• Iron dextran (INFeD, Dexferrum)
• Ferric gluconate (Ferrlecit)
• Ferumoxytol (Ferahem)
• difference in iron (ferric state) core size and carbohydrate polymer determine their pharm. and biologic distinctions
• max dose of these agents varies directly with iron core size

• contains particles with a core of iron surrounded by a core of carbohydrate
• bioactive iron is released slowly form the stable colloid particles

• Given IV only
• less likely than iron dextran to cause hypersensitivity reactions
• must be given in divided doses

• Given IV only
• less likely than iron dextran or possibly sodium ferric gluconate to cause hypersensitivity reactions
• must be given in divided doses

• Consists of a iron oxide coated with a carbohydrate shell
• given IV only
• has potential superparamagnetic for hypersensitivity reactions and hypotension
• total iron dose can be given in 2 divided doses given 3-8 days apart
• as a superparamagnetic iron oxide, it can alter magnetic resonance imaging studies for up to 3 months after last dose

• Dextran carbohydrate shell is associated with severe anaphylactic rxns
• requires a test dose to avoid rxns. (small dose given in office while pt is monitored for rxns)
• total amount required can be given as a slow IV infusion with 0.9% NaCl solution 
• Advantage: can be given all at 1 time
• disadvantage: anaphylactic shock

1. Phosphates
2. ?
3. Magnesium 

• as kidney fxn declines, phosphorus elimination declines, resulting in hyperphosphatemia
• this directly stimulates PTH synthesis and also leads to hypocalcemia (an important stimulus for PTH secretion)
• Phosphate binders are common part of pharmacotherapy in pts with advanced CKD. 

• common pharmacotherapy for pts with advanced CKD
• bind phosphate in the GI tract
• dietary restriction must be exercised
• most effective when given with meals to bind dietary phosphate

• CaCO₃
• Ca acetate (PhosLo)
• Sevelamer (Renagel)
• Lanthanum (Fosrenol)
• Aluminum hydroxide

• Vit D is a cholesterol derivative formed in the skin after exposure to UV light
• must be activated by hepatic and renal enzymes to active form (calcitriol)
• 1st hydroxylation (25-hydroxyvitamin D) occurs in liver. 2nd occures in kidney to produce active form (1,25-hydroxyvitamin D or calcitriol)
• As kidney fxn ↓ 1α-hydroxylase production ↓, resulting in active vitamin D deficiency

• ↑ intestinal Ca²⁺ absorption
• inhibits parathyroid hormone (PTH) synthesis
• indirectly ↓ secretion of PTH by ↑ Ca²⁺ absorption

Actions of Calcitriol are impaired in pts with CKD. Resulting in:

• secondary hyperparathyroidism (SHPT)
• less Ca²⁺ GI absorption
• more bone resorption
• renal osteodystrophy (ROD)

• Calcitriol: active from (give to pts with kidney dysfunction)
• Ergocalciferol (D2): Inactive requires conversion to active form by kidney
• Doxercalciferol (vit D analog)
• Paricalcitol (Vit D analog)

do same as calcitriol 

• may have slight advantage b/c Ca²⁺ and P0₄ may ↑ due to use of calcitriol more often than with analogs
• less hypercalcemia
• less hyperphosphatemia 
• fewer hospitalizations

• Hypercalcemia
• Hyperphosphatemia
• interruption of therapy as a result

• increase the sensitivity of Ca²⁺ sensing receptors in the parathyroid glands to extracellular Ca²⁺ and reduce the secretion of PTH
• Unlike Vitamin D, which is also used to ↓ PTH levels, calcimimetics are less likely to cause a potentially dangerous ↑ in serum Ca²⁺ and PO₄ levels

• GI: Diarrhea (21%0, Nausea (31%), Vomiting (27%)
• endocrine metabolic: Hypocalcemia (8%)
• Cinacalcet inhibits CYP2D6, adjust dose of concomitant drugs metabolized by this pathway

• can produce significant suppression of PTH without exacerbation of hyperphosphatemia
• Hypocalcemia has not been significant